1. Field of the Invention
The invention relates to new polypeptides having lymphotoxin activity or lymphotoxin-like activity, to their preparation and to their use for controlling diseases, where appropriate in combination with lymphokines.
2. Description of Related Art
Lymphotoxin (also called TNF-beta) was described for the first time in 1968 (Ruddle and Waksman J. exp. Med. 128 (1968) 1267-1279; Granger and Kolb J. Immun. 101 (1968) 111-120; Rosenau, W. Fed. Proc. 27 (1968) 34-38). As a biological factor from mitogen-stimulated lymphocytes, lymphotoxin has cytotoxic activity on neoplastic cell lines. It has a spectrum of activities, such as cytostasis of some tumor cell lines and a pronounced cytolytic activity on other transformed cells (Sawada and Osawa Jap. J. Exp. Med. 46 (1976) 263-267; Granger et al. J. Cell. Immun. 38 (1978) 388-402; Rundell and Evans Immunopharmacology 3 (1981) 9-18; Granger et al. J. Lymphokine Res. 1 (1982) 45-49; Ruddle et al. J. Lymphokine Res. 2 (1983) 23-31).
The cytotoxic activity of lymphotoxin on primary cell cultures and normal cell lines is less or nonexistent. These findings led to in vivo studies (Khan et al. Proc. Soc. exp. Biol. Med. 169 (1982) 291-294; Papermaster et al. Cancer 45 (1980) 1248-1253; Ransom et al J. Natn. Cancer Inst. 69 (1982) 741-744) whose results then showed that lymphotoxin is an effective antitumor agent.
Human lymphotoxin has the amino acid sequence depicted in FIG. 1 (Gray et al. Nature 312 (1984) 721-724). The signal sequence of lymphotoxin is labeled -34 to -1 in this figure.
Human lymphotoxin (TNF-beta) belongs to a group of lymphokines which also includes tumor necrosis factor (TNF or TNF-alpha). The two proteins not only have a similar spectrum of actions in vitro and in vivo but also act in each case synergistically with interferon-gamma (Ruddle et al. J. Lymphokine Res. 2 (1983) 23-31, Granger et al. J. Lymphokine Res. 1 (1982) 45-49; Ruff and Giffort, Lymphokines Vol. 2, Pick, E. ed. 235-275 Academic Press New York 1981; Carswell et al. Proc. Natl. Acad. Sci. 72 (1975) 3666-3670; Evans Canc. Immunol. Immunother 12 (1982) 181-190; Rundell and Evans, Immunopharmacology 3 (1981) 9-18; Ruff and Giffort, Infect. Immun. 31 (1981) 380-385; Williamson et al. Proc. Natl. Acad. Sci. 80 (1983) 5397-5401; Williams and Bellanti, J. Immunol. 130 (1983) 518-520; Stone-Wolff et al. J. Exp. Med. 159 (1984) 828-843; Lee et al. J. Immunol. 133 (1984) 1083-1086; Powell et al. J. Lymphokine Res. 4 (1985) 13-26).
The genes for the two proteins are located adjacently on chromosome 6 (Nedwin et al. Nucl. Acid Res. 13 (1985) 6361-6373).
Comparison of the amino acids of the two proteins showed that they have a 30% homology at the amino acid level (FIG. 2). This homology is concentrated on the central and C-terminal parts of the two proteins, whereas the N-terminal ends are heterologous and of different lengths (FIG. 2).
In addition, a lymphotoxin mutant is known and is distinguished from the natural lymphotoxin by the absence of the first 23 amino acids at the N-terminal end.